Urate is the end product of purine metabolism in humans. Humans and higher primates have much higher serum urate levels than other species because they lack the enzyme uricase, which converts urate into its breakdown product allantoin. See Anzai N., et al., “New insights into renal transport of urate,” Curr. Opin. Rheumatol. 19:151-157 (2007). Reduced excretion of urate by the kidney is the main cause for elevated urate levels, Anzai et al., supra, which can lead to gout, a painful condition affecting approximately three million individuals in the United States. See Lawrence R. C., et al., “Estimates of the prevalence of arthritis and other rheumatic conditions in the United States, Part II,” Arthritis Rheum. 58:26-35 (2008).
It is well established that gout is a consequence of elevated serum urate levels. Anzai et al., supra. Yet, medications used to decrease serum urate levels are frequently not effective. Allopurinol, the most commonly used drug to decrease serum urate levels, inhibits the production of urate. Elevated serum urate levels, however, are usually a consequence of impaired renal urate excretion rather than increased urate production.
Renal urate transport is complex and still poorly understood. Anzai et al., supra. Although multiple renal urate transporters have been characterized in model systems, their role in human disease is mostly unclear. To date, it has been difficult to target renal urate secretion pharmacologically, because the molecular identity of the transporters mediating secretion in humans was not known.
Serum urate levels are highly heritable, suggesting a strong genetic component. See Yang Q., et al. “Genome-wide search for genes affecting serum uric acid levels: The Framingham Heart Study,” Metabolism 54:1435-1441 (2005). In a genome-wide association study (GWAS) of serum urate levels, multiple single-nucleotide polymorphisms (SNPs) in a genomic region on chromosome 4 containing the ATP-binding cassette subfamily G member 2 (ABCG2) gene were identified as being associated with urate levels and prevalence of gout. See Dehghan A., et al., “Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study,” Lancet 372:1953-1961 (2008). ABCG2 was first identified as a multidrug resistance protein, see Doyle L. A., et al., “A multidrug resistance transporter from human MCF-7 breast cancer cells,” Proc. Natl. Acad. Sci. USA 95:15665-15670 (1998), and has been shown to transport a wide range of structurally and functionally diverse substrates, such as chemotherapeutics. See Polgar O., et al., “ABCG2: structure, function and role in drug Response,” Expert Opin. Drug Metab. Toxicol. 4:1-15 (2008). Yet, the physiological substrate and the roles of ABCG2 in vivo have remained elusive.